PB2562: STUDY DESIGN OF THE AURORA TRIAL: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF BITOPERTIN IN ERYTHROPOIETIC PROTOPORPHYRIA
Authors: Cynthia Levy, Karl E. Anderson, Manisha Balwani, Herbert L. Bonkovsky, Amy Dickey, Siobán Keel, Brendan Mcguire, Roy Smith, Manish Thapar, Bruce Wang, William Savage
Journal: HemaSphere (2023)

Topic: 29. Iron metabolism, deficiency and overload Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria are caused by pathogenic variants in the ferrochelatase (FECH) or 5-aminolevulinate synthase 2 (ALAS2) genes, respectively, resulting in accumulation of photoreactive protoporphyrin IX (PPIX). In the protoporphyrias, excess PPIX is produced in erythroid cells in the bone marrow and subsequently delivered to the liver in red blood cells and plasma. Elevated levels of PPIX cause debilitating phototoxic skin reactions following exposure to sunlight, and may lead to potentially life-threatening protoporphyric hepatopathy in some patients. Reduction of PPIX is associated with amelioration of disease in the settings of hematopoietic stem cell transplant, pregnancy and extracorporeal photoinactivation. Glycine transporter 1 (GlyT1) supplies extracellular glycine for the initial step of heme biosynthesis in erythroid cells. Bitopertin is an investigational small molecule inhibitor of GlyT1. It is hypothesized that GlyT1 inhibition leads to a decrease in heme pathway intermediates, including PPIX, and can improve light tolerance. In murine models of EPP and XLP, treatment with bitopertin lowered blood PPIX levels by >40% compared to controls. Bitopertin treatment in EPP mice also lowered liver PPIX levels and reduced histopathological evidence of liver cholestasis and fibrosis compared to controls. These data, combined with a favorable safety profile observed in prior clinical studies of bitopertin with cumulative enrollment of > 4,000 participants, provided rationale for the current study. Aims: Evaluate the safety, tolerability, and efficacy of bitopertin in adults with EPP. Efficacy assessments include changes in levels of blood metal-free PPIX, as well as measures of phototoxicity, sunlight tolerance, and pain. Methods: AURORA is a Phase 2, randomized, double-blind, placebo-controlled trial (NCT05308472) that will randomize approximately 75 participants (1:1:1) to receive oral, once-daily administration of 20 mg, 60 mg bitopertin, or placebo for 17 weeks. Participants ≥18 years of age with a confirmed diagnosis of EPP by PPIX analysis and/or genetic testing will be enrolled. Exclusion criteria include AST/ALT values ≥2x the upper limit of normal, hemoglobin <10 g/dL, or concurrent treatment with afamelanotide or dersimelagon. Randomization will be stratified by baseline light tolerance (time to prodrome < or ≥30 minutes), as assessed during a 2-week screening period. The primary efficacy endpoint is percent change in whole blood metal-free PPIX in participants randomized to bitopertin compared to placebo. The key secondary endpoint is the total hours of sunlight exposure to skin on days with no pain from 10:00 to 18:00 hours. Upon completion of the double-blind treatment period, patients may continue in an open-label extension study. Results: The study was initiated in October 2022, and recruitment is ongoing. Enrollment is planned at 10 sites in the United States Summary/Conclusion: The AURORA study is designed to evaluate bitopertin as a potential disease-modifying treatment and will test the hypothesis that bitopertin can reduce PPIX and improve light tolerance in adults with EPP.Keywords: Clinical trial